The present invention relates to processes for the preparation of bicyclic aminoalcohols.
The following scheme is disclosed in Chem. Pharm. Bull., 37(6), 1524-1533 (1989) as processes for the preparation of a bicyclic aminoalcohol (IV). 
A starting material, myrtenol, is reacted with ethyl orthoformate to give an exomethylene derivative. The exomethylene derivative is oxidized by ozone to give a ketone derivative, compound (II-1), which is further reacted with O-methylhydroxyamine to give an O-methyloxime derivative, compound (III-1). The obtained O-methyloxime derivative is reduced in n-propanol with metallic sodium to give a bicyclic aminoalcohol, compound (IV).
It is disclosed in the above document that alkylation of nopinone, compound (I), gives a mixture of the starting material, a di-substituted product and a mono-substituted product as shown below. Moreover, the mono-substituted product is disclosed as a mixture of two stereo isomers. 
There are some problems in the above process for the preparation of the bicyclic aminoalcohol that the starting material, myrtenol, is expensive and not preferable in view of supply. Thus, another process for the preparation of the ketone derivative, compound (II-1), is desired. In the above method, the purity of the bicyclic aminoalcohol (compound (IV)) obtained through reduction of the O-methyloxime derivative (compound (III-1)) is not so high. When the bicyclic aminoalcohol is crystallized and purified as a salt with benzoic acid, the yield is only 39.6%.
A benzothiophene carboxamide derivative, compound (VIII): 
wherein R3 is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl, R4 is hydrogen or alkyl, and a double bond represents E- or Z-configuration, is a high selective PGD2 receptor antagonist. WO 98/25919 discloses the following process for the preparation of the compound (VIII). 
wherein R3 is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl, R4 is hydrogen or alkyl, and a double bond represents E- or Z-configuration.
The bicyclic aminoalcohol of the formula (IV): 
is useful as an intermediate of the compound (VIII) and should be prepared at a low cost and stably provided.
But, a prior art of process for the preparation of the bicyclic aminoalcohol (IV) has the above problems.
On the other hand, as shown below, a method using an alkaline metal- or alkaline earth metal-substituted borohydride in the presence of a Lewis acid is known as a reduction of an O-methyloxime derivative (compound (III-1)) to a bicyclic aminoalcohol (compound (IV)). 
But the above method using such borohydrides is accompanied with production of diborane, so this method has a problem in view of safety for an industrial process.
The present inventors have found out a process for the preparation of the ketone derivative (compound (II)) from nopinone (compound (I)) and a novel process for the reduction of the O-methyloxime derivative or a more inexpensive oxime derivative (compound (III)) to the bicyclic aminoalcohol (compound (IV)), to develop a safe process for the preparation of the bicyclic aminoalcohol.
The present invention provides;
1) a process for the preparation of a compound (II): 
wherein R1 is alkyl, which comprises reacting a compound (I): 
with XCH2COOR1 wherein X is halogen, and R1 is as defined above in the presence of an additive and a base,
2) a process for the preparation of a compound (IV): 
which comprises reducing a compound (III): 
wherein R1 is as defined above, and R2 is hydrogen or alkyl, with an aluminum hydride,
3) a process for the preparation of a compound (IV): 
which comprises reacting a compound (II): 
wherein R1 is as defined above, with NH2OR2 wherein R2 is as defined above to give a compound (III): 
wherein R1 and R2 are as defined above, and reducing the compound (III) with an aluminum hydride,
4) a process for the preparation of a compound (III): 
wherein R1 and R2 are as defined above, which comprises preparing a compound (II): 
wherein R1 is as defined above, through the process according to the above 1), and reacting the compound (II) with NH2OR2 wherein R2 is as defined above,
5) a process for the preparation of a compound (IV): 
which comprises preparing a compound (III): 
wherein R1 and R2 are as defined above through the process according to the above 4), and reducing the compound (III) with an aluminum hydride,
6) the process according to the above 2), 3) or 5) wherein the aluminum hydride is prepared by reacting a Lewis acid with lithium aluminum hydride or reacting concentrated sulfuric acid with lithium aluminum hydride,
7) a process for the preparation of a compound (IX): 
wherein R5 each is independently alkyl, which comprises reacting a compound (I): 
with (R5)3SiX wherein R5 is as defined above, and X is halogen, in the presence of a base,
8) a process for the preparation of a compound (X): 
wherein R6 each is independently alkyl, which comprises reacting a compound (IX): 
wherein R5 each is independently alkyl, with CH2xe2x95x90CHOR6 wherein R6 is as defined above in the presence of ceric ammonium nitrate (IV) in a solvent of R6OH wherein R6 is as defined above,
9) a process for the preparation of a compound (X): 
wherein R6 is as defined above, which comprises preparing a compound (IX): 
wherein R5 is as defined above through the process according to the above 7), and reacting the compound (IX) with CH2xe2x95x90CHOR6 wherein R6 is as defined above in the presence of ceric ammonium nitrate (IV) in a solvent of R6OH wherein R6 is as defined above,
10) a process for the preparation of a compound (VI): 
wherein R3 is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl, which comprises preparing a compound (IV): 
through the process according to any one of the above 2), 3), 5) and 6), and reacting the compound (IV) or its salt with a compound (V): 
wherein R3 is as defined above or its reactive derivative,
11) a process for the preparation of a compound (VII): 
wherein R3 is as defined above, which comprises preparing a compound (VI): 
wherein R3 is as defined above through the process according to the above 10), and oxidizing the compound (VI),
12) a process for the preparation of a compound (VII): 
wherein R3 is as defined above, which comprises preparing a compound (X): 
wherein R6 is as defined above through the process according to the above 8) or 9), reacting the compound (X) with NH2OR2 wherein R2 is as defined above to give a compound (XI): 
wherein R2 and R6 are as defined above, reducing the compound (XI) to give a compound (XII): 
wherein R6 is as defined above, reacting the compound (XII) with a compound (V): 
wherein R3 is as defined above or its reactive derivative to give a compound (XIII): 
wherein R3 and R6 are as defined above, and reacting the compound (XIII) with an acid,
13) a process for the preparation of a compound (VIII): 
wherein R3 is as defined above, R4 is hydrogen or alkyl, and a double bond represents E- or Z-configuration, a pharmaceutically acceptable salt or hydrate thereof, which comprises preparing a compound (VII): 
wherein R3 is as defined above through the process according to the above 11) or 12), reacting the compound (VII) with an ylide of the formula: Ph3Pxe2x95x90CH(CH2)3COOR4 wherein R4 is as defined above, and if desired, deprotecting.
The term xe2x80x9calkylxe2x80x9d includes straight or branched C1 to C6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or the like. Preferred is methyl or ethyl.
The term xe2x80x9cacylxe2x80x9d includes carbonyl substituted with hydrogen or the above alkyl, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl or the like. Preferred is formyl or acetyl.
The term xe2x80x9calkylsulfonylxe2x80x9d includes sulfonyl substituted with the above alkyl, for example, methanesulfonyl, ethanesulfonyl or the like.
The term xe2x80x9carylsulfonylxe2x80x9d includes sulfonyl substituted with aryl. The term xe2x80x9carylxe2x80x9d includes a monocyclic aromatic carbocyclic group or polycyclic aromatic carbocyclic group, for example, phenyl, naphthyl or the like. Aryl may be substituted with the above alkyl. Examples of arylsulfonyl include benzenesulfonyl, p-toluenesulfonyl or the like.
The term xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo or iodo.

wherein R1 is alkyl, R2 is hydrogen or alkyl, and X is halogen.
Step 1
This step shows a process for the preparation of a ketone derivative (compound (II)) from nopinone (compound (I)). A mono-substituted derivative (compound (II)) can be obtained in high yield by reacting a compound (I) with XCH2COOR1 wherein X and R1 are defined above in the presence of an additive and a base, without producing a mixture of the starting material, a di-substituted derivative and a mono-substituted derivative as shown in the above document.
An additive includes a reagent controlling the stereochemistry, such as N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine (TMEDA), hexamethylphosphoramide (HMPA), N,Nxe2x80x2-dimethlpropyleneurea (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI) or the like. Preferred is N,Nxe2x80x2-dimethlpropyleneurea (DMPU) or 1,3-dimethyl-2-imidazolidinone (DMI). The amount of an additive is preferably 0.01 to 10.0 mole equivalent, more preferably 0.5 to 2.0 mole equivalent, and especially 1.0 to 1.5 mole equivalent to the compound (I).
A base includes a lithiation reagent such as lithium diisopropylamide (LDA), n-butyllithium or the like. Preferred is lithium diisopropylamide (LDA). A commercially available LDA may be used. LDA may be prepared by reacting diisopropylamine with n-butyllithium when it is used. The amount of a base is preferably 1.0 to 10.0 mole equivalent, more preferably 1.0 to 3.0 mole equivalent, and especially 1.0 to 1.5 mole equivalent to the compound (I).
XCH2COOR1 wherein X is halogen, and R1 is alkyl, includes ethyl bromoacetate, methyl bromoacetate or the like. Preferred is ethyl bromoacetate. The amount of XCH2COOR1 wherein X and R1 are as defined above is preferably 1.0 to 10.0 mole equivalent, more preferably 1.0 to 5.0 mole equivalent, and especially 2.0 to 3.0 mole equivalent to the compound (I).
The amount of XCH2COOR1 wherein X and R1 are as defined above is preferably larger than that of a base. A preferred amount is: additive 1.0 mole equivalent, base 1.0 to 1.2 mole equivalent and XCH2COOR1 2.0 to 3.0 mole equivalent to the compound (I).
It is preferred in this process that XCH2COOR1 is added to a mixture of the compound (I), an additive and a base. The compound (I), additive and base may be added in any order. For example, the addition can be performed in the order of compound (I), additive and base, or the order of base, additive and compound (I).
The reaction temperature is xe2x88x92100 to 100xc2x0 C., preferably xe2x88x9270xc2x0 C. to room temperature.
The reaction time is 0.5 to 50 hours, preferably 1 to 24 hours.
The reaction solvent includes an ether derivative (e.g., ethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, diethylene glycol dimethyl ether or the like), a hydrocarbon derivative (e.g., toluene, xylene) or a mixed solvent of an ether derivative and a hydrocarbon derivative.
Step 2
This process shows a process for the preparation of an oxime derivative (compound (III)) from a ketone derivative (compound (II)). A compound (III) can be prepared by reacting a compound (II) with NH2OR2 wherein R2 is as defined above.
NH2OR2 wherein R2 is as defined above includes hydroxylamine, O-methylhydroxylamine or the like.
The reaction temperature is 0 to 150xc2x0 C., preferably 50 to 100 xc2x0 C. When NH2OR2 is hydroxylamine, the reaction is preferably carried out under 70xc2x0 C. because the reaction at high temperature causes an isomerization.
The reaction time is 0.5 to 50 hours, preferably 1 to 24 hours.
Step 3
This step includes a process for the preparation of a bicyclic aminoalcohol (compound (IV)) from an oxime derivative (compound (III)). The bicyclic aminoalcohol (compound (IV)) can be prepared in high yield with high stereo selectivity and safety by reducing the oxime and ester parts of the oxime derivative (compound (III)) with an aluminum hydride at the same time.
An aluminum hydride can be prepared by reacting a Lewis acid or concentrated sulfuric acid with lithium aluminum hydride. The preparation can be carried out in the presence of a compound (III) or preferably before the addition of a compound (III).
A Lewis acid includes a halogenated compound such as halogenated tin, halogenated zinc, halogenated aluminum, halogenated titanium, halogenated boron, halogenated beryllium, halogenated zirconium, halogenated nickel or the like (e.g., stannous chloride, stannic chloride, aluminum chloride (AlCl3), zinc chloride (ZnCl2), beryllium chloride (BeCl2), titanium tetrachloride, boron trifluoride, zirconium tetrachloride, nickel dichloride). Preferred is aluminum chloride, zinc chloride or beryllium chloride.
For example, an aluminum hydride (AlH3) is produced in accordance with the following formulae.
3LiAlH4+AlCl3xe2x86x923LiCl+4AlH3
2LiAlH4+H2SO4xe2x86x92Li2SO4+2AlH3+2H2
2LiAlH4+BeCl2xe2x86x92Li2BeH2Cl2+2AlH3
2LiAlH4+ZnCl2xe2x86x922LiCl+ZnH2+2AlH3
The reaction solvent includes ether derivatives (e.g., ethylether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, diethylene glycol dimethyl ether), hydrocarbon derivatives (e.g., toluene, xylene), a mixed solvent of ether derivatives and hydrocarbon derivatives. Preferred is tetrahydrofuran.
The amount of aluminum hydride is preferably 1.0 to 10.0 mole equivalent, more preferably 2.0 to 10.0 mole equivalent, and especially 2.0 to 5.0 mole equivalent to the compound (III).
In the preparation of aluminum hydride, the amount of a Lewis acid, which depends on the kind of Lewis acid, is preferably 0.25 to 2.5 mole equivalent, more preferably 0.5 to 2.5 mole equivalent, and especially 0.5 to 1.25 mole equivalent to the compound (III). In the above case, the amount of lithium aluminum hydride is preferably 0.75 to 7.5 mole equivalent, more preferably 1.5 to 3.75 mole equivalent to the compound (III).
When concentrated sulfuric acid is used for the preparation of aluminum hydride, the amount of concentrated sulfuric acid is preferably 0.5 to 5.0 mole equivalent, more preferably 1.0 to 5.0 mole equivalent, especially 1.0 to 2.5 mole equivalent to the compound (III). In the above case, the amount of lithium aluminum hydride is preferably 1.0 to 10.0 mole equivalent, more preferably 2.0 to 5.0 mole equivalent.
The amount of aluminum hydride is preferably 4.0 mole equivalent to the compound (III). Preferably, the amount of lithium aluminum hydride is 3.0 to 4.0 mole equivalent, and that of aluminum chloride or concentrated sulfuric acid is 1.0 to 2.0 mole equivalent.
The procedure is concretely explained below. Two or more mole equivalent of lithium aluminum hydride to the compound (III) is added to a solvent at 0xc2x0 C. to room temperature. 0.33 to 0.5 mole equivalent of a Lewis acid or concentrated sulfuric acid is added thereto. In this case, the Lewis acid or concentrated sulfuric acid can be dissolved in the solvent in advance. To this suspension is added a starting material (an oxime derivative, compound (III)) dissolved in double or more volume of a solvent. The oxime derivative (compound (III)), lithium aluminum hydride, Lewis acid or concentrated sulfuric acid can be added in any order. Then, the reaction mixture is stirred at 0 to 150xc2x0 C. for a few minutes to hours. The mixture is mixed with water, and a diluted mineral acid (e.g., diluted hydrochloric acid), then stirred for decomposing excess of lithium aluminum hydride or aluminum hydride. The reaction mixture may be poured into to the diluted mineral acid.
Then the mixture is neutralized with an alkali (e.g., sodium hydroxide), extracted with an organic solvent (e.g., ethyl acetate) and evaporated to give a bicyclic aminoalcohol (compound (IV)). If necessary, the purification of bicyclic aminoalcohol (compound (IV)) can be carried out by forming a crystalline salt with an appropriate acid (e.g., benzoic acid) and neutralizing with an alkali.
The desired compound, bicyclic aminoalcohol (compound (IV)) can be prepared in high yield with high stereo selectivity by the above method.
The process for the preparation of bicyclic aminoalcohol described above is novel and useful. As shown below, a combination of this process and the process for the preparation of the final target compound (compound (VIII)) contributes to safe and efficient production of compound (VIII). 
wherein R3 is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl, R4 is hydrogen or alkyl, and a double bond represents E- or Z-configuration.
Step 4
This scheme shows a process for the preparation of an amide derivative (VI) which comprises acylating a bicyclic aminoalcohol (IV) or its salt with a carboxylic acid (V) or its reactive derivative.
The salt of bicyclic aminoalcohol (IV) includes a salt with an organic acid (e.g., benzoic acid) or an inorganic acid (e.g., hydrochloric acid, sulfuric acid).
The carboxylic acid (V) used in the acylation can be synthesized in accordance with a known method in literatures [for example, Nippon-Kagaku Zasshi vol. 88, No. 7, 758-763 (1967); Nippon-Kagaku Zasshi vol. 86, No. 10, 1067-1072 (1965); J. Chem. Soc. (C). 1899-1905(1967); J. Heterocycle. Chem. vol.10, 679-681(1973)].
The term xe2x80x9creactive derivativexe2x80x9d of carboxylic acid (V) refers to corresponding acid halides (e.g., chloride, bromide, iodide), acid anhydrides (e.g., mixed acid anhydride with formic acid or acetic acid), activated esters (e.g., succinimide ester), and the like, and includes acylating agents generally used for the acylation of amino group. For example, to obtain acid halides, a carboxylic acid is reacted with thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride), or the like, according to a known method (e.g., Shin-jikken Kagaku Koza, vol. 14, p. 1787 (1978); Synthesis 852-854(1986); Shin-jikken Kagaku Koza vol. 22, p. 115 (1992)).
The acylation can be carried out under ordinary conditions used for the acylation of amino group. For example, when a carboxylic acid halide is used, the reaction is carried out according to a method commonly known as xe2x80x9cSchotten-Baumann reactionxe2x80x9d. In general, carboxylic acid halide is added dropwise to an aqueous alkaline solution of amine with stirring and under cooling while removing the generating acid with alkali. Alternatively, when a carboxylic acid is used as a free acid not a reactive derivative, the reaction can be conducted conventionally in the presence of a coupling agent generally used in the coupling reaction between an amine and a carboxylic acid, such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide or N,Nxe2x80x2-carbonyldiimidazole.
Step 5
This step is related to the oxidation of an alcohol (VI) to an aldehyde (VII). Such a reaction can be conducted by using an oxidizing agent of chromium oxide type such as Jones reagent, Collins reagent or pyridinium chlorochromate. Further, oxidation with manganese dioxide or Swern oxidation with dimethyl sulfoxide are also applicable.
The other oxidation can be carried out with an oxidizing agent(s) such as halo oxoacid in the presence of TEMPO. Examples of TEMPO include 2,2,6,6-tetramethyl-piperidine-1-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and 4-cyano-2,2,6,6-tetramethylpiperidine-1-oxyl. Examples of halo oxoacid include sodium hypochlorite, sodium hypobromite, sodium bromite and higher bleaching powder.
Step 6
This step is related to the formation of a double bond by reacting an aldehyde (compound (VII)) with an ylide (Ph3Pxe2x95x90CH(CH2)3COOR4 wherein R4 is hydrogen or alkyl).
The reaction forming a double bond can be carried out in a conventional manner for Wittig reaction. The ylides used in the reaction can be synthesized, in the presence of a base, from a phosphonium salt which has been synthesized from triphenylphosphine and an alkyl halide having a desired alkyl group to be condensed, for example, 5-bromopentanoic acid. Preferred is Ph3Pxe2x95x90CH(CH2)3COOH.
Examples of a base include dimsyl sodium, dimsyl potassium, sodium hydride, n-butyl lithium, potassium t-butoxide and lithium diisopropylamide. The reaction is accomplished within several hours at room temperature in a solvent such as ether, tetrahydrofuran, n-hexane, 1,2-dimethoxyethane or dimethyl sulfoxide.
The double bond of the alkenylene side chain (5-heptenylene chain) on a compound (VIII) may be in the E- or Z-configuration.
A compound wherein R3 is hydrogen can be prepared by deprotecting R3 under an acidic condition (e.g., hydrochloric acid, sulfuric acid, boron tribromide), a neutral condition (e.g., trimethylsilyl iodide) or a basic condition (e.g., sodium hydroxide, potassium hydroxide, barium hydroxide). The reaction is accomplished within several tens minutes to several hours with heating in a solvent such as methanol-water, ethanol-water, acetone-water, acetonitrile-water, or the like, preferably dimethyl sulfoxide-water. The OR3 may be positioned at any of 4-, 5-, 6- and 7-positions and preferably at 5-position.
The compound (VIII) prepared from the above processes can be formed into a salt. Examples of the salt include alkali metal salts such as lithium salt, sodium salt or potassium salt and the like, alkali earth metal salts such as calcium salt and the like, ammonium salt, salts with an organic base such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthalenemethylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene, 2-aminoanthracene, dehydroabiethylamine, N-methylmorpholine or pyridine, or amino acid salts such as lysine salt or arginine salt.
A hydrate of a compound (VIII) or its salt includes monohydrate, dihydrate, monohydrate of sodium salt, monohydrate of half calcium salt, dihydrate of half calcium salt or the like. 
wherein R2 is hydrogen or alkyl, R5 each is independently alkyl, R6 is alkyl, R3 is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl, and X is halogen.
Step 7
This step is related to the preparation of a silyl ether (compound (IX)) by reacting nopinone (compound (I)) with a compound of the formula: (R5)3SiX wherein R5 each is independently alkyl, and X is halogen, in the presence of a base.
A base includes a lithiation agent such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide. The amount of a base is 1.0 to 2.0 mole equivalent, especially 1.0 to 1.5 mole equivalent to the compound (I).
A compound of the formula: (R5)3SiX includes chlorotrimethylsilane, bromotrimethylsilane, chlorotriethylsilane or the like. The amount of a compound of the formula: (R5)3SiX is 1.0 to 2.0 mole equivalent, especially 1.0 to 1.5 mole equivalent to the compound (I).
The present reaction is accomplished within several hours to several tens hours under xe2x88x92100xc2x0 C. to 100xc2x0 C., especially xe2x88x9270xc2x0 C. to room temperature.
In the present step, a compound (I), a base and a compound of the formula: (R5)3SiX can be added in any order. Preferably, a base is added under cooling to compound (I), and the mixture is stirred for several minutes to several hours, followed by adding a compound of the formula: (R5)3SiX. After the addition of a base, the mixture can be warmed up to approximately 0xc2x0 C., cooled, and mixed with a compound of the formula: (R5)3SiX.
The reaction solvent includes a non-polar solvent such as tetrahydrofuran, dioxane, diethyl ether or the like.
Step 8
This step is related to the preparation of a compound (X) by reacting a silylether derivative (compound (IX)) with a compound of the formula: CH2xe2x95x90CHOR6 wherein R6 is alkyl, in the presence of ceric ammonium nitrate (IV) in a solvent of R6OH wherein R6 is as defined above.
A compound of the formula: CH2xe2x95x90CHOR6 includes methyl vinyl ether (R6 is methyl), ethyl vinyl ether (R6 is ethyl), n-propyl vinyl ether (R6 is n-propyl), n-butyl vinyl ether (R6 is n-butyl), vinyl acetate (R6 is acetyl) or the like. The amount of a compound of the formula: CH2xe2x95x90CHOR6 is 1.0 to 30.0 mole equivalent, especially 10.0 to 20.0 mole equivalent to the compound (IX).
R6OH includes an alchol having R6 corresponding to R6 of a compound of the formula: CH2xe2x95x90CHOR6 used in the present step. When a compound of the formula: CH2xe2x95x90CHOR6 is methyl vinyl ether, ethyl vinyl ether, n-propyl vinyl ether and n-butyl vinyl ether, R6OH is methanol, ethanol, n-propanol and n-butanol, respectively.
The amount of ceric ammonium nitrate (IV) is 1.0 to 5.0 mole equivalent, especially 1.0 to 2.0 mole equivalent to the compound (IX).
Preferably, this step is performed in the presence of a base. Examples of a base include calcium carbonate, sodium carbonate, sodium hydrogen carbonate or the like. The amount of a base is 1.0 to 5.0 mole equivalent, especially 1.0 to 3.0 mole equivalent to the compound (IX).
The present reaction is accomplished within several hours to several tens hours under xe2x88x92100xc2x0 C. to 100xc2x0 C., especially 0xc2x0 C. to room temperature.
In the present step, a compound (IX), a base, ceric ammonium nitrate (IV), R6OH and a compound of the formula: CH2xe2x95x90CHOR6 can be added in any order. Preferably, a compound (IX) and a compound of the formula: CH2xe2x95x90CHOR6 are added under cooling to a solution of a base and ceric ammonium nitrate (IV) in a solvate of R6OH.
Step 9
This step is related to the preparation of an oxime derivative (compound (XI)) by reacting a ketone derivative (compound (X)) with NH2OR2 wherein R2 is as defined above. This step can similarly be performed in accordance with STEP 2.
Step 10
This step is related to the preparation of a compound (XII) by reducing an oxime derivative (compound (XI)) with a reducing agent.
The present reduction should be carried out under a condition not influencing the group of the formula: xe2x80x94CH(OR6)2 of the compound (XI). Preferred is a reduction under a basic condition, for example, reduction with sodium metal in alchol.
The reaction temperature is xe2x88x92100xc2x0 C. to 100xc2x0 C., especially xe2x88x9250xc2x0 C. to 50xc2x0 C.
Step 11
This step is related to the preparation of a compound (XIII) by reacting a compound (XII) with a carboxylic acid (V) or its reactive derivative. The present step can similarly be performed in accordance with STEP 4.
Step 12
This step is related to the preparation of an aldehyde derivative (compound (VII)) by hydrolyzing a group of the formula: xe2x80x94CH(OR6)2 of the compound (XIII).
This hydrolysis can be carried out preferably under an acidic condition at xe2x88x92100xc2x0 C. to 100xc2x0 C., specially 0xc2x0 C. to room temperature. The reaction time is several minutes to several tens hours.
The compound (VII) prepared in this step is identical to a compound (VII) prepared in STEP 5. A compound (VIII) can be prepared through STEP 6 by using the compound (VII).